Cutting Edge: TGF-β-Induced Expression of Foxp3 in T cells Is Mediated through Inactivation of ERK

Abstract

The peripheral induction of T regulatory cells can be accomplished by TGF-β through an epigenetic regulation leading to the expression of Foxp3. However, the exact mechanism of such a TGF-β-mediated action remains unclear. In the current study, we found that TGF-β treatment of CD4+CD25− T cells during T cell activation led to a transient inhibition of the phosphorylation of ERK followed by the induction of Foxp3 expression in these cells. Direct treatment with a specific ERK inhibitor, UO126, during CD4+CD25− T cell activation also induced Foxp3 expression and conferred a suppressive function to the induced Foxp3+ T cells. Furthermore, treatment of T cells with either TGF-β or UO126 significantly down-regulated the expression of DNMTs, a reaction normally elicited by demethylation agents, such as 5-Aza-2′-deoxycytidine. These results indicate that the epigenetic regulation of TGF-β-induced expression of Foxp3 may be mediated through the inactivation of ERK.

Inhibition of hyaluronan synthesis restores immune tolerance during autoimmune insulitis

“…This is consistent with a previous report that ERK1/2 inhibition promotes FOXP3 induction (24). However, these data do not preclude a role for other pathways.…”

Atorvastatin upregulates regulatory T cells and reduces clinical disease activity in patients with rheumatoid arthritis

“…However, acquisition of the T reg phenotype does not exclusively mean the conversion of T reg from human T cells because we also observed a population of nonsuppressive T cells with the phenotype of T reg in the absence of AT, and previous research has reported a tran- pathways, which regulate FoxP3 expression in activated naïve T cells ( 37,38 ), have been demonstrated to be regulated by AT in some systems ( 39,40 ). In our study, we observed that AT inhibited the phosphorylation of ERK and PI3K-Akt-mTOR and U0126 (ERK inhibitor) or LY294002 (PI3K-Akt inhibitor) treatment of activated primary T cells mimicked the effects of AT on T reg .…”

Increased Foxp3+ Regulatory T Cells in Poly(ADP-Ribose) Polymerase-1 Deficiency

“…PARP-1 might regulate Foxp3 gene expression by acting on chromatin structure, by regulating the activity of transcription factors, or by modulating signal transduction events (31). PARP-1 was described to interact with and be phosphorylated by Erk1/2 (32, 33), which also plays a role in Treg cell differentiation (34). Differences between the results obtained in experiments with PARP-1 KO mice and with the use of PARP inhibitors demonstrated that PARP-1 can regulate the activity of target molecules by different mechanisms.…”